Resistance to currently available antibiotics has created a need for new antibiotic agents. Infections, caused by organisms such as Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecium and Enterococcus faecalis, have become increasingly resistant to currently approved antibiotics. For example, significant clinical problems include methicillin-resistant strains of S. aureus, which are resistant to all current antibiotics except vancomycin (a drug of last resort because of severe side effects), and a vancomycin-resistant strain of E. faecium enterococci which is now found world-wide. Even community-acquired organisms such as Streptococcus pneumoniae are increasingly resistant to antimicrobial agents, with a significant number of isolates being resistant to penicillin and extended-spectrum cephalosporins.
The emergence and spread of resistant bacterial organisms are primarily caused by acquisition of drug resistance genes, resulting in a broad spectrum of antibiotic resistance (e.g., extended-spectrum cephalosporin-resistant mutant .beta.-lactamases found in several bacterial organisms). Genetic exchange of multiple-resistance genes, by transformation, transduction and conjugation; combined with selective pressures in settings such as hospitals where there is heavy use of antibiotic therapies, enhance the survival and proliferation of antimicrobial agent-resistant bacterial strains occurring by, e.g., spontaneous mutants. Although the extent to which bacteria develop resistance to antimicrobial drugs and the speed with which they do so vary with different types of drugs, resistance has inevitably developed to all antimicrobial agents (see Gold and Moellering, Jr., 1996, New Eng. J. Med., 335(19):1445–1453).
To prevent or delay the buildup of a resistant pathogen population, different chemicals that are effective against a particular disease-causing bacterium must be available. Thus, there is a need to identify compounds which can penetrate and specifically kill the pathogenic bacterial cell, or arrest its growth without also adversely affecting its human, animal, or plant host.
One avenue for accomplishing this task involves the use of compounds targeting RNA polymerase. Accordingly, what is needed in the art are new compounds which are effective inhibitors of bacterial RNA polymerase and which are useful as antibacterial agents. The present invention provides such compounds along with methods for their use.